Identification of the Pyruvate dehydrogenase kinase 2 structure complexed with inhibitors targeting the ATP-binding and lipoamide binding site

Abstract

The pyruvate dehydrogenase kinase (PDK) inactivates the human pyruvate dehydrogenase complex (PDC) by phosphorylation. The PDC regulates mitochondrial metabolism as a gatekeeper by converting the pyruvate to CO2 and acetyl-CoA. The high expression level of PDK leads the excessively inactivated PDC, triggering the metabolic disorders. To treat the diseases, inhibitors of PDK have been developed, although they need to be optimized for efficacy and specificity. Here, we present the crystal structures of PDK2 complexes with GM10030, GM67520, and compound 8c, respectively. The GM10030 and the GM67520 have the core, 4-phenyl-5-(5- chlororesocinyl)isoxazole-3-carboxamido, that primarily contributes to binding the ATP pocket. Notably, GM67520 occurs the conformational change of ATP lid that may increase the binding affinity. The compound 8c, a lypoyl-binding pocket targeting inhibitor, is newly introduced to have an anthraquinone moiety that is sandwiched with two phenylalanines. We suggest our structural study is helpful to optimize inhibitors and drug discoveries.